1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

6q24 Transient Neonatal Diabetes Mellitus (6q24 TNDM or TNDM1); Diabetes Mellitus, Transient Neonatal (TND, DMTN); Imprinted transient neonatal diabetes (iTND).

1.2 OMIM# of the disease

601410.

1.3 Name of the analysed genes or DNA/Chromosome segments

6q24; PLAGL1 Imprinting control region (ICR); ZFP57.

1.4 OMIM# of the gene(s)

PLAGL1, 603044; HYMAI, 606546; ZFP57, 612192.

1.5 Mutational spectrum1, 2

1.6 Analytical methods

DNA methylation analysis can be performed by ASMM RTQ-PCR; MS-MLPA (SALSA kit ME032 (MRC-Holland, Amsterdam, The Netherlands)); MS-PCR, bisulphite pyrosequencing, MS-SnuPE and methylation array.3, 4, 5, 6, 7 Copy number imbalance can be detected by MS-MLPA, short tandem repeat marker typing and molecular karyotyping (SNP array, aCGH), and in the case of rare large duplications, FISH or cytogenetic analysis. Uniparental disomy analysis can be performed by short tandem repeat marker typing or by molecular karyotyping using SNP array (UPD testing should preferentially include the parents for full informativity).

1.7 Analytical validation

Parallel analysis of negative (unaffected) and positive (affected) controls. Determination of methylation and copy number reference ranges in unaffected individuals (for methylation of same tissue type). For methylation analysis fully (in vitro) methylated and unmethylated (eg, whole-genome amplification) controls should be included.

1.8 Estimated frequency of the disease

1:300 000.8

1.9 Diagnostic setting

Comment: Prenatal testing may in principle be requested, in cases of familial chromosomal rearrangements potentially affecting the copy number of PLAGL1 or leading to UPD of this region, as well as in cases of familial ZFP57 mutations. In practice, the rarity of the disorder makes prenatal testing extremely rare. In principle, prenatal testing for genomic disturbances (duplications, point mutations) can be offered without limitations and can support clear genetic counselling. Prenatal methylation-specific testing is not common, due to insufficient knowledge about the prenatal setting of the PLAGL1 imprinting mark. Special consideration of recurrence risk is required for the rare maternal effect mutations in NLRP2, NLRP7 or KHDC3L (see Section 3.4).

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present to the best of our knowledge at the moment given that the condition is so rare)

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)

Nearly 100%.

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present)

70–80%.

Note that neonatal diabetes is genetically heterogeneous and, besides the 6q24-linked form described in this gene card, includes other monogenetic forms.9, 10, 11 Mutations of ABCC8 (MIM#600509) and KCNJ11 (MIM#600937) account for 30% of TNDM, but have a distinct clinical history, with less-extreme low birthweight, and later onset and remission.2, 10 Moreover, forms of permanent NDM exist. If these monogenetic forms being part of the differential diagnoses are not considered, the sensitivity (ie, 6q24 aberration detected by test if the disease is present) is estimated to be 70–80%

2.4 Clinical specificity

(proportion of negative tests if the disease is not present)

Nearly 100%.

2.5 Positive clinical predictive value

(lifetime risk to develop the disease if the test is positive)

A small number of cases (n=3 in a cohort of 163 cases) have been described where individuals with 6q24 TNDM mutations did not present neonatally, but subsequently, with disorders such as insulin resistance or gestational diabetes.12, 13 Owing to the rarity of the disorder, the lifetime risk of later presentation in these individuals is not established.

Note that diabetes presenting at birth resolves in the first few months of life. Earlier clinical studies indicated that 50% of individuals presenting neonatally with 6q24 TNDM would subsequently develop a disorder akin to type 2 diabetes, in later childhood or adulthood,14 but there is no definitive research to confirm this.

2.6 Negative clinical predictive value

(Probability not to develop the disease if the test is negative)

Index case in that family had been tested:

Approaching 100%, where the proband has a positive diagnosis of a 6q24 anomaly.

Index case in a family that has not been tested:

<80%.

Where a proband has a clinical diagnosis of transient neonatal diabetes but no molecular diagnosis has been performed, then the molecular cause may be 6q24 aberration, or mutation in ABCC8/KIR6.2. In a hyperglycaemic infant under 6 months of age, molecular diagnoses of both transient and permanent neonatal diabetes should be considered.9

3. Clinical Utility

3.1 (Differential) diagnostics: The tested person is clinically affected

(To be answered if in 1.9 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

A diagnosis of neonatal diabetes can be made clinically in infants under 6 months of age, with combined biochemical and immunological (absence of antibodies, no HLA-association) analysis; however, genetic diagnosis is warranted for differentiating 6q24 TNDM from other (monogenic) causes of TNDM where clinical history and management are different.9 Moreover, molecular testing enables differential diagnosis at manifestation (when the transient nature is not known) between transient and permanent neonatal diabetes.

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Classifying 6q24 TNDM is useful for targeting appropriate management of neonatal hyperglycaemia.9, 15

3.1.4 Will disease management be influenced by the result of a genetic test?

3.2 Predictive setting: The tested person is clinically unaffected but carries an increased risk based on family history

(To be answered if in 1.9 ‘B’ was marked)

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe):

Yes.

If the test result is positive, there is an 50% risk of non-insulin-dependent diabetes developing in adolescence or adulthood. The predisposing factors are not fully understood, but diabetes may be precipitated by metabolic stresses such as puberty, pregnancy, illness or predisposing lifestyle factors. Therefore, those very rare individuals with a positive test result but without neonatal presentation (Section 2.5) should be vigilant for signs of incipient diabetes.

If the test result is negative (please describe):

No.

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?

(i) In a pedigree with an intrachromosomal duplication of PLAGL1, a male has a 50% risk of transmitting a duplicated allele to offspring, whether his own duplication was maternally or paternally transmitted. In case of interchromosomal changes leading to gain of 6q24 the segregation might be dependent on the size of the exchanged fragments. Carriers of a balanced translocation affecting chromosome 6 have an increased risk for their offspring carrying an unbalanced aberration of 6q24, which in case of paternal gain leads to 6q24 TNDM. Similarly, there is theoretically an increased risk for UPD(6q24)pat due to trisomy/monosomy rescue. (ii) In a pedigree with ZFP57 mutation, homozygous individuals are at risk of 6q24 TNDM.

3.3 Genetic risk assessment in family members of a diseased person

Most molecular aberrations in 6q24 TNDM are sporadic (UPD(6q24)pat and the majority of PLAGL1 hypomethylation cases).1 In these cases, family members are at only population risk. However, for chromosomal aberrations leading to duplication of 6q24 and ZFP57 mutation, there is a risk to family members. Homozygous mutations of ZFP57 and paternal inheritance of 6q24 duplication both carry in principle 100% risk of 6q24 TNDM (though non-penetrance is observed, see earlier). Also balanced chromosome 6 aberrations in one of the parents lead to an increased risk for 6q24 TNDM as part of gain affecting 6q24 or UPD derived from malsegregation and rescue, respectively. In patients with MLMD, maternal effect mutations might lead to an up to 100% recurrence risk in offspring.

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

Yes.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Yes.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Yes.

3.4 Prenatal diagnosis

(To be answered if in 1.9 ‘D’ was marked)

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?

Yes, although see caveat regarding methylation testing. However, due to the rarity of the disorder information is very scarce at present.

4. If applicable, further consequences of testing

Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)

The identification of a mutation or epimutation allows delineation of recurrence risk for the patient and his or her family as well as indicating risk of diabetes recurrence in later life.